Scientific efforts focused on the delivery of oligonucleotides systemically for therapeutic purposes are ongoing. Three highlighted approaches to oligonucleotide delivery include 1) lipid nanoparticle (LNP) encapsulation, 2) polymer conjugation and 3) single chemical conjugation. Single chemical conjugation typically employs a targeting ligand or a lipid or a solubilizing group or an endosomolytic peptide or a cell penetrating peptide and/or a combination of two or all four attached to an oligonucleotide. Linkers may be present in the conjugate as well as other functionalities. Single chemical conjugates are known and attachment of the oligonucleotide occurs either at the 5′- or 3′-end of the oligonucleotide, at both ends, or internally. See WO2005/041859; WO2008/036825 and WO2009/126933.
The single chemical conjugates of the instant invention must contain a peptide, which may be considered an endosomolytic component, cell penetrating peptide and/or a fusigenic peptide, at the 5′- and/or 3′-end of the oligonucleotide. Linkers must be present between the peptide and the oligonucleotide as well. Other functionalities, such as targeting ligands, solubilizing agents, lipids, and/or masking agents are optionally present. Typically the oligonucleotide is an siRNA. Further the oligonucleotide is the passenger strand or the guide strand of the siRNA.